Multiple sclerosis (MS) can be divided into four clinical forms: relapsing-remitting (RR), primary progressive (PP), secondary progressive (SP) and progressive relapsing (PR). The pathogenesis of the progressive forms of MS remains unclear, partly due to the lack of animal models that have these clinical patterns of disease. Using an encephalitogenic peptide from myelin oligodendrocyte glycoprotein (MOG)92-106, we have established animal models that mimic the different forms of MS in two strains of MHC identical H-2s mice, SJL/J and A.SW. We induce experimental allergic encephalomyelitis (EAE) with (MOG)92-106 in the presence or absence of supplemental Bordetella pertussis (BP). SJL/J mice develop RR-EAE whether BP was administered or not. Interestingly, A.SW mice develop PP-EAE without BP and SP-EAE with BP supplementation. Histologically, SJL/J mice develop a mild demyelinating disease with extensive T cell infiltration, while A.SW mice develop large plaque-like demyelinating lesions with immunoglobulin deposition and neutrophil infiltration, associated with very minimal T cell infiltration. In A.SW mice without BP, high titer serum anti-MOG antibody is detected and the anti-MOG IgG2a/IgG1 ratio correlated with survival times of the mice. We hypothesize that, in A.SW mice, a Th2 response favors the production of myelinotoxic antibodies, leading to progressive forms of EAE with early death, while a Th1 response in SJL mice favors a RR form with longer survival. To test this hypothesis, four specific aims are proposed. The first aim will study the role of NK1.1+ T cells in progressive disease. The second aim will determine whether IL-4 is responsible for the T helper (Th) 2 phenotype and progressive EAE seen in A.SW mice sensitized with (MOG)92-106. The third aim will be to investigate the role of anti-myelin antibodies in disease progression and contribution to lesion formation. The fourth and last aim will study other factors involved in progressive disease such as environmental and genetic contributions. These new models could help explain the transition from RR disease to progressive disease often observed in MS patients.